ABSTRACT Current clinical photodynamic therapy (PDT) is an effective cancer treatment that is non-invasive and low- cost, but it has yet to become a mainstream, frontline treatment. The clinical efficacy of PDT in solid tumors depends on significant accumulation of the photosensitizer (PS) at the tumor site, availability of oxygen near the photosensitizer, and effective dosing of the drug-light combination. Our new platform for delivery and imaging of photosensitizers, entitled nano-enabled PDT (nePDT), will enhance all three of these areas, raising PDT?s therapeutic index and enabling PDT to reach its full clinical potential. nePDT comprises a core of oxygen-rich liquid perfluorocarbon (PFC) containing indocyanine green (ICG) dye stabilized by a lipid shell which houses the photosensitizer (PS) and also provides binding sites for cancer cell targeting antibodies. The ICG dye is used to trigger a liquid to gas phase change of the PFC which serves two purposes: (1) it delivers PS and additional O2 to the cell cytosol (acting as a nanosyringe) and (2) the vaporization event creates a giant acoustic transient which can be detected using combined photoacoustic and ultrasound (PAUS) imaging and used to visualize the distribution of drug delivery at the tumor site. From the rich 3D spatial information received by PAUS imaging of the drug distribution, light intensity and duration dosimetry for effective PDT can be calculated. This personalized dosimetry will ensure patients receive the correct therapy dose customized for their tumor. The promise of PDT to provide localized therapy with minimal residual damage or side effects to healthy tissues is remarkable. We are excited to introduce this new nePDT platform that will enhance specific delivery of PS to the tumor, increase efficacy of therapy through O2 delivery (especially to hypoxic tumors), and ultimately create a personalized patient specific dose enabled by PAUS imaging. While PDT has the potential to treat a variety of diseases, we chose head and neck cancer generally, and specifically oral cancer, for an initial target application due to the unmet clinical need for minimal intervention, minimal scarring to reduce cosmetic and functional defects, and the superficial location of these tumors which provides light accessibility. nePDT is a revolutionary new nanoplatform capable of removing the roadblocks to widespread therapeutic efficacy and clinical success for PDT.